Synthesis and Cytotoxic Activity of Combretastatin A-4 and 2,3-Diphenyl-2H-indazole Hybrids.

Cancer is the second leading cause of death, after cardiovascular diseases. Different strategies have been developed to treat cancer; however, chemotherapy with cytotoxic agents is still the most widely used treatment approach. Nevertheless, drug resistance to available chemotherapeutic agents is still a serious problem, and the development of new active compounds remains a constant need. Taking advantage of the molecular hybridization approach, in the present work we designed, synthesized, and tested the cytotoxic activity of two hybrid compounds and seven derivatives based on the structure of combretastatin A-4 and 2,3-diphenyl-2H-indazole. Practical modifications of reported synthetic protocols for 2-pheny-2H-indazole and 2,3-dipheny-2H-indazole derivatives under microwave irradiation were implemented. The cytotoxicity assays showed that our designed hybrid compounds possess strong activity, especially compound 5, which resulted even better than the reference drug cisplatin against HeLa and SK-LU-1 cells (IC50 of 0.16 and 6.63 µM, respectively), and it had similar potency to the reference drug imatinib against K562 cells. Additionally, in silico and in vitro studies strongly suggest tubulin as the molecular target for hybrid compound 5.

Blood cadmium determinants among males over forty living in Mexico City.

BACKGROUND: Mexico City has air, water and food pollution problems; however, human exposure to cadmium and its sources have not been described. OBJECTIVES: To determine the blood cadmium (BCd) level and its main exposure sources among males aged 40 years or older living in different areas of Mexico City. METHODS: After receiving informed consent, we interviewed 702 males aged ≥40 years to collect data on their sociodemographic characteristics, lifetime occupation, smoking history, and dietary habits, using a validated questionnaire. The BCd level (µg/L) was determined by atomic absorption spectrophotometry. RESULTS: The BCd mean level ±â€¯SD was 2.61 ±â€¯0.82 µg/L, and 20% of men reported a potential cadmium occupational exposure. After adjusting for age and other potential confounders, the main determinants of the BCd level were the current smoking status at interview, with low (ß≤8.5packs/year vs. non-smoker = 0.46; 95% CI: 0.28-0.64 µg/L; p < 0.01) and high (ß> 8.5 packs/year vs. non-smoker = 0.71; 95% CI: 0.56-0.87 µg/L; p < 0.01) smoking intensity, and living in the Center (ßCenter vs. South = 0.20; 95% CI: 0.02-0.37 µg/L; p = 0.02) or West area of the city (ßWest vs. South = 0.40, 95% CI: 0.21-0.58 µg/L; p < 0.001). Moreover, the potential dietary sources of BCd included: liver (ßYes vs. No = 0.13, 95% CI: 0.03-0.23 µg/L; p = 0.01), "Chorizo" (ß>1-3servings/month vs. No = 0.14, 95% CI: 0.01-0.26 µg/L; p < 0.001), sausage and ham. CONCLUSIONS: The BCd levels observed in this population are high and only similar to those observed in workers from a sanitary landfill area in Southern Thailand. Potential environmental Cd exposure sources, such as industrial activity and previous land use, in the West and Center areas of the city should be explored in detail, especially in vulnerable population groups, such as children.